Lung cancer is the leading cause of cancer death in the United States and worldwide, accounting for over 150,000 deaths per year in the United States and over 1 million deaths per year world-wide. Non-small cell lung cancer accounts for slightly over 80% of all lung cancer cases. Therefore the development of novel targeted therapeutics for non-small cell lung cancer is of great clinical and public health importance. In recent years, the advent of targeted cancer therapies has led to major advances in the prognosis and survival of cancer patients. Our applicant group has contributed to one of the most dramatic of these advances, the deployment of EGFR inhibitors for patients whose lung cancers bear activating EGFR mutations. This has led to significant advances in treatment of such patients, as demonstrated in this last year by several clinical trials. Nevertheless, as shown by the still-grim mortality statistics, the efforts that lie in front of us far exceed the accomplishments that we and other investigators have achieved to date. The goal of this integrated research Program is to advance the scientific underpinnings of targeted therapies for non-small cell lung cancer. Specifically, we will generate and characterize genetically engineered mouse models based on each of the lung cancer kinase targets (EGFR, TBK1 and DDR2). We will then perform in vivo therapeutic efficacy studies using these mouse models and the appropriately matched targeted therapeutics generated in this Program. Lastly, we will perform in vivo chronic treatment studies with the mouse models and molecule inhibitors to determine in vivo mechanisms of acquired resistance.